Project Summary/Abstract There has been increasing recognition over the last several years of the heterogeneity in the pathobiologic underpinnings of asthma and the critical importance of phenotyping and endotyping in dictating response to therapy. For example, it was only after selecting patients with sputum (and later blood) eosinophilia and using exacerbation rate as the primary outcome, was the utility of mepolizumab in asthma uncovered in a clinical trial setting. With multiple immune-modulating biologic agents already available and with more to come in the very near future, our understanding how to best deploy these agents in a precise manner to patients with severe and/or exacerbation-prone asthma (those who would be most likely to be prescribed biologic agents) must be refined. The PrecISE Network will use sequential, adaptive clinical trial designs, which represents a novel approach in asthma clinical research, to answer these questions, while also presenting an opportunity for significant progress in phenotyping and endotyping as applied to clinical management of patients with severe asthma. In this application, we propose the following Specific Aims: 1) Establishment of the San Diego Team Asthma Management Program (STAMP) as a Clinical Center in the NHLBI PrecISE Network: We have put together a team that leverages the substantial resources of UCSD and the San Diego region to create a PreCISE Clinical Center that will optimally recruit subjects and perform PrecISE Network protocols as they are developed and implemented. 2) Proposal of a PrecISE Netowrk Clinical Trial Using a sequential, adaptive, phase IIb/proof of concept design: In accordance with the goals of the PrecISE Network, our proposed trial design will be center on the use of precision interventions based on stratification of severe asthma subjects by phenotype/endotype. Using already established biomarkers, including blood/sputum eosinophilia, serum periostin, serum IgE, and exhaled NO, we propose to stratify subjects into Th2-high (?Th2H?), non-Th2-high (?NTh2H?), and MIXED endotypes to dictate experimental interventions. Th2H and MIXED subjects would be randomized to placebo, Allakos (Anti-Siglec-8 monoclonal antibody), or dupilumab (anti-IL4/IL13 receptor). Concurrently, NTh2H subjects would be randomized into placebo, etanercept (TNF inhibitor), or dupilumab. During the trial, some of these interventions may be shown to have a lack of sufficient activity and these will be withdrawn after interim analysis and replaced by new agents or by new biomarker-defined groups. Successful treatments at the interim analysis stage will proceed to the next stage. 3) Identification of novel biomarkers to stratify responders to targeted treatments: Our group has the scientific expertise to perform and analyze novel biomarker studies associated with PrecISE protocols. We propose to leverage these micro-scaled genomic and immunology tools to identify novel biomarkers for treatment response from sputum and blood samples of our study subjects.